The aim of this study was to assess the role of glucose metabolism via the sorbitol pathway in mediating increased blood flow in transgenic mice (6-8 wk. of age) overexpressing skeletal muscle GLUT-1. Blood flow was assessed soleus, epitrochlearis (epi), and gastrocnermius (gastroc) muscles by iv injection of 3H-desmethylimipramine (DMI, a plasma soluble tracer, mol wt=276) and expressed as a ratio (X(SD, n=8-9 mice per group) of DMI content in muscle/retina (a tissue not overexpressing GLUT-1). Muscle sorbitol levels were quantified by GCMS as their butylboronate derivatives. These observations suggest an important role for increased flux of glucose via the sorbitol pathway in mediating increased blood flow in skeletal muscles overexpressing GLUT-1. These findings also attest to marked differences in sorbitol pathway metabolism in skeletal muscles, and in blood flow changes in skeletal muscles overexpressing GLUT-1, independent of plasma insulin and glucose levels.